Protozoa of the genus Trypanosoma and Leishmania are known to cause a number of diseases in animals and humans. These protozoa can be transmitted by blood feeding invertebrates, by mechanical vectors or venereally, and are responsible for a number of diseases known as trypanosomosis or trypanosomiasis and leishmaniasis. Animal African Trypanosomosis (AAT), Human African Trypanosomiasis (HAT), Chagas disease and leishmaniasis are such parasitic diseases, which result in significant morbidity and mortality.
Animal trypanosomosis or African animal trypanosomosis (AAT) is one of the most significant infectious threats to cattle and other livestock in sub-Saharan Africa, and it also is also widespread in Asia and South America. African animal trypanosomosis (AAT) remains one of the biggest infectious disease constraints to productive livestock rearing in sub-Saharan Africa. AAT is also becoming increasingly prevalent beyond this region and is an established threat to animal health in South America and Asia. Trypanosomes are spread by the bite of infected tsetse flies (Glossina species). Certain Trypanoxome species can be mechanically transmitted by biting flies or by venereal transmission. Animal trypanosomosis clinical symptoms vary from per-acute to chronic and include intermittent fever, anaemia, weight loss, hypertrophy of lymph nodes, oedema, hemorrhages, rough hair coat, lacrimation, abortion, sterility, and reduction in draught power. Death often follows in animals not treated effectively. There are veterinary trypanocidal drugs, based on several families of compounds, however, most were developed more than 50 years ago, that are used for treatment and chemoprophylaxis. Widespread resistance is reported against the available trypanocidal drugs. Many of the current drugs for animal trypanosomosis have poor therapeutic indices and there are concerns about their human safety (meat and milk residues and exposure of administrators to the drug). All of these current therapies have deficiencies, including resistance and safety, and new trypanocidal agents are urgently needed.
Human African trypanosomiasis (HAT), also known as sleeping sickness, is transmitted by the tsetse fly (Glossina genus) which have acquired their infection from human beings or from animals harboring the human pathogenic parasites. In the early stages of HAT, the trypanosomes multiply in subcutaneous tissues, blood and lymph. This is also called the hemo-lymphatic stage, which produces bouts of fever, headaches, joint pains and itching. In the advanced stage of HAT, the parasites cross the blood-brain barrier to infect the central nervous system, known as the neurological or meningo-encephalic stage. Symptoms include changes of behavior, confusion, sensory disturbances, poor coordination and sleep disturbances. Without treatment, sleeping sickness is considered fatal. Several drugs are used to treat the early and advanced stages of HAT, however, the treatments are marred by toxicities (including fatalities), complex and difficult administration, low response rates, resistance and narrow therapeutic indices.
A different form of human trypanosomiasis occurs mainly in Latin America and is known as American trypanosomiasis or Chagas disease, caused by the T. cruzi trypanosome species. Chagas is vector-borne by contact with feces or urine of blood-sucking triatomine bugs (insects), known as kissing bugs. Chagas disease occurs mainly in the continental part of Latin America, but has been increasingly detected in the United States, Canada, and many European and some Western Pacific countries. Chagas disease presents itself in two phases. The initial, acute phase lasts for about 2 months after infection. During the acute phase, a high number of parasites circulate in the blood but in most cases symptoms are absent or mild. In less than 50% of people bitten by a triatomine bug, characteristic first visible signs may be a skin lesion or a purplish swelling of the lids of one eye. Additionally patients may present with fever, headache, enlarged lymph glands, pallor, muscle pain, difficulty in breathing, swelling, and abdominal or chest pain. During the chronic phase, the parasites are hidden mainly in the heart and digestive muscles. Up to 30% of patients suffer from cardiac disorders and up to 10% suffer from digestive (typically enlargement of the esophagus or colon), neurological or mixed alterations. In later years the infection may lead to sudden death or heart failure caused by progressive destruction of the heart muscle and the nervous system. Chagas disease can be treated with benznidazole and also nifurtimox. Both medicines are effective in curing the disease if given soon after infection at the onset of the acute phase including the cases of congenital transmission. The efficacy of both drugs diminishes, however, the longer a person has been infected.
Leishmaniasis is a disease caused by protozoa of the genus Leishmania. Primary hosts are mammals, including human and rodents. Typically, Leishmaniasis results from Leishmania transmission by the bite of certain species of sand fly (e.g. Phiebotominae and Lutzomyi). The human disease is zoonotic (i.e transmissible from non-human animals), but some can be spread between humans. There are three main forms of leishmaniases—visceral (the most serious form of the disease), cutaneous (the most common), and mucocutaneous. Visceral leishmaniasis (VL; caused by L. donovani), also known as kala-azar is fatal if left untreated in over 95% of cases. It is characterized by irregular bouts of fever, weight loss, enlargement of the spleen and liver, and anemia. It is highly endemic in the Indian subcontinent and in East Africa. An estimated 200,000 to 400,000 new cases of VL occur worldwide each year. Over 90% of new cases occur in six countries: Bangladesh, Brazil, Ethiopia, India, South Sudan and Sudan. Post-kala-azar dermal leishmaniasis (PKDL) is a sequel of visceral leishmaniasis that appears as macular, papular or nodular rash usually on face, upper arms, trunks and other parts of the body. It occurs mainly in East Africa and the Indian subcontinent. It usually appears 6 months to 1 or more years after kala-azar has apparently been cured, but may occur earlier. People with PKDL are considered to be a potential source of kala-azar infection. Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis and causes skin lesions, mainly ulcers, on exposed parts of the body, leaving life-long scars and serious disability. About 95% of CL cases occur in the Americas, the Mediterranean basin, the Middle East and Central Asia. Over two thirds of new CL cases occur in 6 countries: Afghanistan, Algeria, Brazil, Colombia, Iran and the Syrian Arab Republic. Mucocutaneous leishmaniasis leads to partial or total destruction of mucous membranes of the nose, mouth and throat. Almost 90% of mucocutaneous leishmaniasis cases occur in Bolivia, Brazil and Peru. The current treatments suffer from safety/toxicity concerns (including cardiotoxicty), incomplete cure rates, difficult administration, long duration of treatment, lack of compliance and developing resistance. (Disease descriptions and facts were obtained from www.who.org).
Consequently, there remains a need to develop effective therapeutic agents for the infectious diseases and their symptoms described above.
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